The Role of SPARC during Toxoplasma infection in the Brain

描述（由申请方提供）：历史上，大脑被认为是免疫特权部位，几乎没有免疫监视。我们现在知道，有持续的监测，但炎症反应需要严格控制。虽然这种控制的机制已经被广泛研究，但重点主要是细胞的进入，而不是对大脑中一旦存在的炎症的控制。弓形虫是世界上最常见的人类感染之一，在美国的流行率为10-30%，在欧洲和南美洲的部分地区有80%的人感染。这种原生动物寄生虫导致CNS中的慢性感染，在大脑中需要持续的炎症反应以维持潜伏期，如死于弓形虫脑炎的免疫受损个体所示。然而，没有明显的病理学与大脑中这种持续存在的炎症有关。因此，T.弓形虫导致大脑中的免疫反应足够强大，以提供对寄生虫的保护，但又足够控制，以防止免疫病理学。这使得能够研究在CNS中实现良好平衡的免疫应答的机制。该提案研究了感染期间脑内T细胞迁移的控制。我们最近的研究表明，感染后，T细胞在其上迁移的网状网络形成。为了阐明涉及这种迁移的机制，将进行实验，观察一种被称为“酸性和富含半胱氨酸的分泌蛋白质”（SHP）的分泌糖蛋白。该分子与CNS中的发育过程、细胞外基质沉积和外周中细胞迁移增加相关，然而先前在脑中的炎症反应期间尚未得到证实。弓形虫感染后，CNS中与寄生虫和炎症相关的抗体显著增加。该提议检验了以下假设：在对弓形虫的免疫应答过程中，脑内的白细胞迁移是必要的，并有助于白细胞迁移。了解外周细胞如何被引导至感染部位并仍然防止CNS中的免疫病理学与控制影响大脑的感染性病原体直接相关。此外，它还可能导致新的机制来对抗在许多神经退行性疾病中普遍存在和致病的炎症。 公共卫生相关性：本提案研究弓形虫感染期间大脑中炎症反应的调节。这是人类最常见的病原体之一，但在缺乏适当的免疫反应的情况下，可能导致致命的脑炎。了解弓形虫感染期间大脑中的免疫调节，除了控制大脑中的感染外，还可以提供新的机制来对抗神经退行性疾病期间普遍存在的炎症。

DESCRIPTION (provided by applicant): Historically the brain was considered an immune-privileged site with little immune- surveillance. We now understand that there is continuous surveillance but that inflammatory responses need to be tightly controlled. Although the mechanisms of this control have been extensively researched the focus has been primarily on the entry of cells and less about the control of inflammation once present in the brain. Toxoplasma gondii is one of the most common human infections in the world with prevalence rates in the USA at 10-30% and with 80% of people infected in parts of Europe and South America. This protozoan parasite leads to a chronic infection in the CNS with a continuous inflammatory response required in the brain to maintain latency as demonstrated in immune-compromised individuals who succumb to Toxoplasmic encephalitis. Yet there is no apparent pathology related to this continuous presence of inflammation in the brain. Thus, T. gondii leads to an immune response in the brain robust enough to provide protection against the parasite but sufficiently controlled to prevent immunopathology. This enables investigations into the mechanisms that achieve a well-balanced immune response in the CNS. This proposal investigates the control of T cell migration within the brain during infection. Recent studies of ours have demonstrated that following infection; the presence of a reticular network is formed on which T cells migrate. To elucidate the mechanism involved in this migration experiments will be conducted looking at a secreted glycoprotein called "secreted protein acidic and rich in cysteine" (SPARC). This molecule has been associated with developmental processes in the CNS, extracellular matrix deposition and increased cell migration in the periphery, however has not previously been demonstrated during inflammatory responses in the brain. Following Toxoplasma infection there is a significant increase in SPARC in the CNS associated with parasites and inflammation. This proposal tests the hypothesis that SPARC is necessary and facilitates leukocyte migration in the brain during the immune response to Toxoplasma. Understanding how peripheral cells are directed to the site of infection and still prevent immunopathology in the CNS has direct relevance to controlling infectious pathogens that affect the brain. In addition, it may also lead to novel mechanisms to counter the inflammation that is prevalent and causative in many neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: This proposal investigates the regulation of the inflammatory response in the brain during Toxoplasma infection. This is one of the most common human pathogens however, in the absence of an appropriate immune response can lead to fatal encephalitis. Understanding immune regulation in the brain during Toxoplasma infection, in addition to controlling infection in the brain, may provide novel mechanisms to counter inflammation that is prevalent during neurodegenerative diseases.